Studies of epoxide formation from drugs (phenytoin and carbamazepine) and related compounds (naphthalene) with aromatic structures indicate that toxicity may be related to epoxide formation, and that diepoxides may be more toxic than monoepoxides. The types of metabolites of greatest interest in this series with respect to potential toxicity are monoepoxides, diepoxides, dihydrodiol epoxides, catechols and quinones. The effects of induction (phenobarbital and beta-naphthoflavone) on the formation of potentially toxic metabolites will be studied. In vivo (rat, mouse) toxicity of metabolites will be defined; in vitro procedures will also be used (Ames tests). Additional work will be carried out on the methylthio pathway of metabolism; this may be a new pathway of elimination for epoxides. The formation of N-hydroxy metabolites from these drugs and from pronethalol will also be studied. Methods for the isolation and study of N-hydroxy compounds are still under development. The synthesis of suspected metabolites will be compared with as yet unidentified drug metabolites.